José G. Guillem, Andrew Berchuck, Jeffrey F. Moley, Jeffrey A. Norton, Sheryl G. A. Gabram-Mendola, and Vanessa W. Hui
INTRODUCTION
Since the heritable component of some cancer predispositions has been linked to mutations in specific genes, clinical interventions have been formulated for mutation carriers within affected families. The primary interventions for mutation carriers for highly penetrant syndromes, such as multiple endocrine neoplasia (MEN), familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (CRC), and hereditary breast and ovarian cancer syndromes, are primarily surgical. This chapter is divided into five sections addressing breast (S.G.A.G.), gastric (J.N.), ovarian and endometrial (A.B.), and MENs (J.F.M.) and colorectal (J.G.G., V.W.H.). For each, the clinical and genetic indications and timing of prophylactic surgery and its efficacy, when known, are provided.
Prophylactic surgery in hereditary cancer is a complex process, requiring a clear understanding of the natural history of the disease and variance of penetrance, a realistic appreciation of the potential benefit and consequence of a risk-reducing procedure in an otherwise potentially healthy individual, and the long-term sequelae of such surgical intervention, as well as the individual patient’s and family’s perception of surgical risk and anticipated benefit.
PATIENTS AT HIGH RISK FOR BREAST CANCER
Identification of Patients at Risk
A detailed family history is the most important tool for identifying individuals at increased risk for hereditary cancers. The US Preventive Services Task Force updated their recommendation for risk assessment, genetic counseling, and genetic testing for asymptomatic women who have not been diagnosed with a BRCA-related cancer. In this update, the use of a risk screening tool is highly recommended to identify appropriate patients for referral for genetic counseling.1 The American Society of Clinical Oncology has also updated the policy on genetic and genomic testing for cancer susceptibility, and this update includes information on genetic tests of uncertain clinical utility and direct-to-consumer marketing, both of which impact the practice of oncology and preventive medicine.2 Historically, genetic counseling and testing were offered by health-care providers. However, with the advent of direct-to-consumer marketing, individuals may obtain tests and receive results directly from a company. The American Society of Clinical Oncology still endorses pre- and posttest counseling for thorough disclosure of the impact of testing. Before any woman considers risk-reduction surgery such as bilateral mastectomy or salpingo-oophorectomy, referral to a high-risk or genetic screening program is desirable, as women often overestimate their actual breast cancer risk.3
The most common cancer syndromes that place women at risk for breast cancer are BRCA14 and BRCA25 gene mutations. Other less common syndromes are listed in Table 32.1.6,7
Following referral for genetic assessment, three groups of patients emerge.8 The first consists of those women who have undergone genetic testing and have been found to harbor a mutated gene associated with high penetrance for breast cancer. Given that the possibility of developing breast cancer in this group may be as high as 90%, there is a role for enhanced surveillance or risk-reduction surgery. The American Cancer Society has published guidelines for magnetic resonance imaging (MRI) screening as a method for enhanced surveillance.9 Women in this first group qualify for such screening, which can be offered annually but scheduled at 6-month intervals with screening mammography to increase the rate of identifying interval cancers. Alternatively, simultaneous screening with MRI and mammography to compare one modality with the other on an annual basis may also be offered. Another choice for this group of women is to pursue bilateral risk-reduction mastectomy with an option for immediate reconstruction. Bilateral salpingo-oophorectomy for BRCA1 and BRCA2 mutation carriers may also be considered, as this procedure has been shown to reduce breast cancer risk by almost 50%.8,10 This is especially true for BRCA2 mutation carriers, who tend to develop hormone receptor–positive breast cancers.
The second group consists of women with strong family histories suggestive of hereditary breast cancer who test negative for both the BRCA1 and BRCA2 mutations as well as the other described syndromes. In this group, there may not have been a family member with cancer who was tested for the mutation. Therefore, a negative test does not necessarily indicate that a woman’s risk is equivalent to that of the general population.7 There may also be an undetected mutation in such a family, indicating the possibility of higher-than-average risk for that particular woman. These women may or may not qualify for enhanced surveillance with MRI screening,9 and accurate assessment of their risk may require the use of other risk prediction tools,3 in addition to evaluating for the presence of lobular carcinoma in situ, atypical lobular hyperplasia, or atypical ductal hyperplasia, and determining if a more intensive surveillance regimen is necessary based on heterogeneously or extremely dense breast tissue on mammography.
The third group consists of women with a strong family history of breast cancer, who for various reasons, have chosen not to pursue genetic testing. These individuals may have other health-related problems, psychological concerns, cost issues, or they may fear perceived medical insurance discrimination. Women in all groups can be educated that with passage of the Genetic Information Nondiscrimination Act in 2008, significant advances have occurred that protect patients from discrimination by employers and health insurers.11
Women in the second and third groups may still qualify for bilateral risk-reduction mastectomy and immediate reconstruction. Often, women who elect this path are influenced by their family history or by witnessing breast and/or ovarian cancer deaths in close family members, giving them a significant fear of a breast or ovarian cancer diagnosis. For women in all three groups, the decision of whether to pursue risk-reducing surgery is difficult. Often, the expertise of a cancer clinical psychologist or psychiatrist is enlisted, as risk-reduction mastectomy involves an irreversible procedure with body image and sexual implications.8
Updated in 2007, the Society of Surgical Oncology published a position statement on the role of prophylactic mastectomy for patients at high risk for breast cancer, as well as those patients recently diagnosed with breast cancer who are considering contralateral prophylactic breast surgery.12 For women at high risk, indications fall into three broad categories: presence of a mutation in BRCA or other susceptible genes, strong family history with no demonstrable mutation, and histologic risk factors (biopsy-proven atypical ductal hyperplasia, atypical lobular hyperplasia, or lobular carcinoma in situ especially in patients with a strong family history of breast cancer). Recommendations for patients with recently diagnosed breast cancer are similar in that they include the indications for high-risk individuals previously noted, as well as future surveillance challenges for the opposite breast (clinically and mammographically dense breast tissue or diffuse, indeterminate microcalcifications in the contralateral breast). Another important consideration is the need for symmetry in patients with large, ptotic, or disproportionately sized contralateral breasts.
Surgical Issues and Technique
In a single institution’s 33-year experience,13 the risk for breast cancer in both moderate- and high-risk groups of women based on family history was reduced by at least 89% for women who underwent bilateral prophylactic mastectomy. From a technical perspective, in this study, women either had a subcutaneous mastectomy (removal of the majority of breast tissue with sparing of the nipple–areola complex) or total mastectomy (removal of the entire breast through the nipple–areola complex). Most of the recurrences occurred in women undergoing a subcutaneous mastectomy. However, this was the most frequent procedure performed at that time and thus may have contributed to the number of increased recurrences.
Another surgical option for high-risk women is bilateral salpingo-oophorectomy. Among a cohort of women with BRCA1 and BRCA2 mutations, this procedure has been associated with a lower risk of mortality from both breast and ovarian cancer.10 As an additional benefit, this procedure also decreases the risk of breast cancer in this patient population, likely through the mechanism of decreasing hormonal exposure at a younger age.
Contemporary surgical procedures for risk-reducing bilateral mastectomy include total mastectomy, skin-sparing mastectomy (preservation of the skin envelope by removal of the entire breast through a circumareolar incision around the nipple–areola complex), subcutaneous mastectomy, areola-sparing mastectomy (removal of the nipple while sparing the areola), and nipple-sparing mastectomy (removal of entire breast and nipple core tissue but preservation of nipple–areolar skin).14 Given advances in reconstructive nipple–areolar techniques, it appears that total mastectomy with or without skin-sparing methods reduces the risk of breast cancer to the greatest extent with reasonable cosmesis. More limited and long-term follow-up data are available on areola- and nipple-sparing techniques. The potential limitations of these procedures are distortion of the nipple–areola complex and lack of sensitivity after breast tissue has been completely removed.8
Immediate reconstruction is offered to patients and performed in the vast majority undergoing bilateral risk-reduction mastectomy. Choices of reconstruction include a bilateral pedicled or free tissue transverse rectus abdominis muscle flap, a free bilateral deep inferior epigastric perforator flap or superficial inferior epigastric artery flap, bilateral latissimus flaps with or without implant or expanders, or bilateral implant or expander placement alone.14Although tissue flap transfer gives a more natural appearance and texture to the reconstructed site, individual body contour drives the ultimate plan for reconstruction. The decision about the type of reconstruction should be made by the plastic surgeon with input from the surgical oncologist, especially for the group of women with breast cancer desiring bilateral mastectomies who may require adjuvant radiation for treatment.
Although the risk reduction is dramatic for bilateral mastectomy, residual breast tissue may be left behind, especially with skin-sparing procedures. Patients should be educated that careful chest wall surveillance is recommended after such a procedure. Local recurrences after bilateral implant reconstruction are reliably detected by clinical examination. Recurrences after reconstruction with autologous tissue present most commonly on the skin 50% to 72% of the time and are detectable by physician examination.15 Nonpalpable deeper recurrences in this setting are less common, and use of mammography image surveillance may be indicated, especially if significant breast tissue was left behind unintentionally during the bilateral mastectomy procedure. At times, an initial “screening” mammogram may be performed, if significant residual breast tissue is suspected; this should occur well after all healing has taken place to delineate the amount of visible breast tissue on imaging. This drives future decisions of whether to follow a patient with imaging. Finally, all patients should be instructed to return for clinical breast examination with the health provider if any change is noted on the reconstructed breasts, regardless of imaging plan.
Although risk-reduction bilateral mastectomy may be exceedingly beneficial for high-risk women, especially for those testing positive for BRCA1, BRCA2, or other deleterious mutations, or belonging to a family afflicted with a cancer syndrome, they are never emergent procedures. Along with risk-reduction bilateral salpingo-oophorectomy, risk-reduction bilateral mastectomy resides at the far end of the spectrum of an individual’s choices.16 These procedures should be offered only after appropriate genetic counseling and accurate assessment of a woman’s actual risk for breast and ovarian cancer. An in-depth consultation with the patient and her family members is necessary prior to proceeding with an operative plan.
HEREDITARY DIFFUSE GASTRIC CANCER
Gastric cancer is the fourth most common cause of cancer worldwide and is the second leading cause of cancer mortality.17 Although environmental agents, including Helicobacter pylori and diet, are the primary risk factors for this disease, approximately 10% of gastric cancers are a result of familial clustering.18,19 Histologically, gastric cancers may be classified as either intestinal or diffuse types. The intestinal type histopathology is linked to environmental factors and advanced age. The diffuse type occurs in younger patients and is associated with a familial predisposition. Because of a decrease in intestinal-type gastric cancers, the overall incidence of gastric cancer has declined significantly in the past 50 years. However, the incidence of diffuse gastric cancer (DGC), which is also called signet ring cell or linitis plastica, has remained stable and, by some reports, may be increasing.
Hereditary DGC (HDGC) is a genetic cancer susceptibility syndrome defined by one of the following: (1) two or more documented cases of DGC in first- or second-degree relatives, with at least one diagnosed before the age of 50; or (2) three or more cases of documented DGC in first- or second-degree relatives, independent of age of onset. The average age of onset of HDGC is 38, and the pattern of inheritance is autosomal dominant.20 Figure 32.1 shows a pedigree with HDGC.
In 1998, inactivating germline mutations in the E-cadherin gene CDH1 were identified in three Maori families, each with multiple cases of poorly differentiated DGC.21 The CDH1 mutations in these families were inherited in an autosomal dominant pattern, with incomplete but high penetrance. Onset of clinically apparent cancer was early, with the youngest affected individual dying of DGC at the age of 14.21Since then, germline mutations of CDH1 have been identified in 30% to 50% of all patients with HDGC.19,22 More than 50 mutations have been recognized across diverse ethnic backgrounds, including European, African American, Pakistani, Japanese, Korean, and others.19 In addition to gastric cancers, germline CDH1 mutations are associated with increased risk of lobular carcinoma of the breast, and this was the first manifestation of a CDH1 mutation in one series.23 CDH1 is, to date, the only gene implicated in HDGC. Penetrance of DGC in patients carrying a CDH1 mutation is estimated at 70% to 80%, but may be higher. The need for a systematic study of specimens is supported by recent work by Gaya et al.24 in which initial total gastrectomy specimens were reported as negative, but detailed sectioning and analysis showed invasive carcinoma.
CDH1 is localized on chromosome 16q22.1 and encodes the calcium-dependent cell adhesion glycoprotein E-cadherin. Functionally, E-cadherin impacts maintenance of normal tissue morphology and cellular differentiation. It is hypothesized that CDH1 acts as a tumor suppressor gene in HDGC, with loss of function leading to loss of cell adhesion and subsequently to proliferation, invasion, and metastases. Figure 32.2 shows the CDH1 mutation for the pedigree depicted in Figure 32.1.
The germline CDH1 mutation is most frequently a truncating mutation. Germline missense mutations are causative in a few HDGC kindreds, but are more often clinically insignificant. In vitro assays for cellular invasion and aggregation may predict the functional impact of missense mutations to aid in this distinction.22 Within the gastric mucosa, the “second hit” leading to complete loss of E-cadherin function results from CDH1 promoter methylation, as has been described in sporadic gastric cancer.25
It remains unclear whether specific CDH1 mutations are associated with distinctive phenotypic characteristics or rates of penetrance, although this may become apparent as more recurrent mutations are recognized. To date, most mutations identified have been novel and distributed throughout CDH1. Recognition of recurrent mutations has usually resulted from independent events; however, there is evidence for the role of founder effects in certain kindreds.22At present, it is also unclear whether patients with HDGC without detectable CDH1 mutations have mutation of a different gene or merely a CDH1 mutation that has gone unrecognized.
New recommended screening criteria for CDH1 mutations are as follows:
1. Families with one or more cases of DGC
2. Individuals with DGC before the age of 40 years without a family history
3. Families or individuals with cases of DGC (one case below the age of 50 years) and lobular breast cancer
4. Cases where pathologists detect in situ signet ring cells or pagetoid spread of signet ring cells adjacent to diffuse type gastric cancer18,26
As in other familial cancer syndromes, genetic counseling should take place prior to genetic testing so that the family understands the potential impact of the results. After obtaining informed consent, a team comprising a geneticist, gastroenterologist, surgeon, and oncologist should discuss the possible outcomes of testing and the management options associated with each. Genetic testing should first be performed on a family member with HDGC or on a tissue sample if no affected relative is living. In addition to direct sequencing, multiplex ligation-dependent probe amplification is recommended to test for large genomic rearrangements. If a CDH1 mutation is identified, asymptomatic family members may proceed with genetic testing, preferably by the age of 20.19 If no mutation is identified in the family member with DGC, the value of testing asymptomatic relatives is low.
Among individuals found to carry a germline CDH1 mutation, clinical screening is problematic. Histologically, DGC is characterized by multiple infiltrates of malignant signet ring cells, which may underlie normal mucosa.27Because these malignant foci are small in size and widely distributed, they are difficult to identify via random endoscopic biopsy. Chromoendoscopy and positron emission tomography have reportedly been used, but the clinical utility of these tools in early detection remains unproven. Lack of a sensitive screening test for HDGC makes early diagnosis extremely challenging. By the time patients are symptomatic and present for treatment, many have diffuse involvement of the stomach or linitis plastica, and rates of mortality are high. Published case reports describe patients who have presented with extensive DGC despite recent normal endoscopy and negative biopsies.28 The 5-year survival rate for individuals who develop clinically apparent DGC is only 10%, with the majority dying before age 40.
Because of high cancer penetrance, poor outcome, and inadequacy of clinical screening tools for HDGC, prophylactic total gastrectomy is recommended as a management option for asymptomatic carriers of CDH1 mutations.18Although total gastrectomy is performed with prophylactic intent in these cases, most specimens have been found to contain foci of diffuse signet ring cell cancer.19,28,29 Foci of DGC have been identified even in patients who have undergone extensive negative screening, including high-resolution computed tomography, positron emission tomography scan, chromoendoscopy-guided biopsies, and endoscopic ultrasonography.19 However, HGDC in asymptomatic CDH1 carriers is usually completely resected by prophylactic gastrectomy, as pathologic analyses of resected specimens have shown only T1N0 disease.
Because these signet ring cell cancers are multifocal and distributed throughout the entire stomach, especially in the cardia,30 prophylactic gastrectomy should include the entire stomach, and the surgeon must transect the esophagus and not the proximal stomach. Furthermore, it should be performed by a surgeon experienced in the technical aspects of the procedure and familiar with HDGC. In asymptomatic patients, lymph node metastases have not been observed; therefore, D2 lymph node resection is not necessary. The optimal timing of prophylactic gastrectomy in individuals with CDH1 mutations is unknown, but recent consensus recommendations indicate that age 20 is reasonable.18
Although it is a potentially lifesaving procedure, prophylactic gastrectomy for CDH1 mutation carries significant risks that must be considered. Overall mortality for total gastrectomy is estimated to be as high as 2% to 4%, although it is estimated to be 1% when performed prophylactically. Patients must also be aware that there is a nearly 100% risk of long-term morbidity associated with this procedure, including diarrhea, dumping, weight loss, and difficulty eating.19 A recent study of the effects of prophylactic gastrectomy for CDH1 mutation demonstrated that physical and mental function were normal at 12 months, but specific digestive issues were recognized. Overall, 70% had diarrhea, 63% fatigue, 81% eating discomfort, 63% reflux, 45% eating restrictions, and 44% had altered body image, suggesting that this operation impacted negatively on quality of life.31 Because of these complications and the fact that lymph node spread has not been observed, some recommend vagus-preserving gastrectomy done either open or laparoscopically. In addition, because the penetrance of CDH1 mutations is incomplete, some patients who undergo prophylactic gastrectomy would never have gone on to develop clinically significant gastric cancer. Prophylactic gastrectomy has, in fact, been performed on several patients reported to show no evidence of gastric cancer on pathology.29
Some individuals with CDH1 mutations choose not to pursue prophylactic gastrectomy. These individuals should undergo careful surveillance, including biannual chromoendoscopy with biopsies, beginning when they are at least 10 years younger than the youngest family member with DGC was at time of diagnosis. It is recommended that any endoscopically visible lesion is targeted and that six random biopsies are taken from the following regions: antrum, transitional zone, body, fundus, and cardia. Careful white-light examination with targeted and random biopsies combined with detailed histopathology can identify early lesions and help to inform decision making with regard to gastrectomy.32 Additionally, because women with CDH1 mutations have a nearly 40% lifetime risk of developing lobular breast carcinoma, they should be carefully screened with annual mammography and breast MRI starting at age 35.23 They should also do monthly self-examinations and have a breast examination by a physician every 6 months. The same surveillance recommendations are probably appropriate for HDGC families without identifiable CDH1mutations, although no current guidelines for this exist.
The emergence of gene-directed gastrectomy as a treatment strategy for patients with HDGC represents the culmination of a successful collaboration between molecular biologists, geneticists, oncologists, gastroenterologists, and surgeons. It is anticipated that the recognition of similar molecular markers in other familial cancer syndromes will transform the approach to the early diagnosis and treatment of a variety of tumors.
SURGICAL PROPHYLAXIS OF HEREDITARY OVARIAN AND ENDOMETRIAL CANCER
Hereditary Ovarian Cancer (BRCA1, BRCA2)
Inherited mutations in BRCA1 and BRCA2 strongly predispose women to breast cancer and to high-grade serous cancers of the ovary, fallopian tube, and peritoneum.33,34 About two-thirds are due to BRCA1mutations and one-third BRCA2 mutations, and these account for about 15% to 20% of high-grade serous cases. The lifetime risk of these gynecologic cancers increases from a baseline of 1.5% to about 15% to 25% in BRCA2 carriers and 30% to 60% in BRCA1 carriers.33,34 BRCA1/2 mutations are rare in most populations (<1 in 500 individuals); one notable exception is the Ashkenazi Jewish population, in which the carrier frequency is 1 in 40.35 BRCA1-associated cases peak in the 50s and BRCA2-associated cancers in the 60s.36 In addition to BRCA1/2 mutations, germline mutations in a number of other genes in the homologous recombination DNA repair pathway confer high penetrance susceptibility to ovarian cancer (e.g., RAD51C, RAD51D, BRIP1, PALB2).37 This has led to the development of more comprehensive cancer genetic testing panels that are increasingly being used to identify women who are candidates for risk-reducing salpingo-oophorectomy (RRSO).
Genetic testing for inherited high-penetrance mutations in BRCA1/2 and other genes should be discussed with women who have a significant family history of early onset breast cancer and/or cancers of the ovary, fallopian tube, or peritoneum. Involvement of a genetic counselor prior to testing is helpful, as they have expertise in managing the inherent clinical and social issues. Most BRCA1/2 mutations involve base deletions or insertions in the coding sequence or splice sites that encode truncated protein products that are clearly dysfunctional. Less frequently, disease-causing mutations may occur that alter a single amino acid, though most of these missense variants represent innocent polymorphisms. The clinical significance of missense mutations can sometimes be elucidated by determining whether they segregate with cancer in other family members. In addition, genomic rearrangements may occur that inactivate BRCA1 or BRCA2, and identification of such alterations requires molecular testing beyond sequencing.
Penetrance of ovarian cancer is not 100% in those with clearly deleterious BRCA1/2 mutations, but presently it is not possible to provide more precise personalized risk estimates to guide the use of RRSO. However, common variants have been discovered in other genes that appear to affect the risk of ovarian cancer in BRCA1/2 carriers.38 Based on the known ovarian cancer risk–modifying loci, it has been reported that the 5% of BRCA1 carriers at lowest risk have a lifetime risk of ≤28% of developing ovarian cancer, whereas the 5% at highest risk have a ≥63% lifetime risk. In the future, when modifier loci are more completely catalogued, more precise estimates of cancer risk may be provided to individual patients who are considering RRSO.
As about 20% of women with high-grade serous ovarian cancers have BRCA1/2 mutations, it has been suggested that all of these women undergo genetic testing regardless of family history.39 Mutational analysis in women with these cancers may increasingly become standard practice as the cost of genetic testing declines. Testing may also be driven by the availability of poly(ADP-ribose) polymerase inhibitor therapy for women whose cancers have germline or sporadic mutations in genes such as BRCA1/2 and others that are involved in homologous recombination DNA repair.
RRSO is strongly recommended in women who carry BRCA1/2 mutations because of the high mortality rate of ovarian cancer and the lack of effective screening and prevention approaches. Although screening with pelvic ultrasound and serum CA125 is generally recommended for BRCA1/2 carriers during their 20s and 30s, it is not proven to reduce ovarian cancer mortality because even early stage high-grade cancers have a very high mortality. Oral contraceptives reduce the risk of ovarian cancer in the general population and appear to have a similar effect in BRCA1/2 carriers, but this must be balanced against concerns regarding increased breast cancer risks.
The past practice of performing RRSO based solely on family history has been replaced by reliance on genetic testing. Clinical management of women with a strong family history in whom a deleterious germline mutation is not found, or those with variants of uncertain significance, should be resolved on a case-by-case basis. RRSO may be deemed appropriate in some cases, despite the absence of a clearly deleterious mutation. Fortunately, the risk of hereditary ovarian cancer does not rise dramatically until the mid-30s in women with BRCA1 mutations and the 40s for women with BRCA2 mutations.36 As a result, most women are able to complete childbearing prior to undergoing RRSO. It is advisable for BRCA1 carriers to undergo RRSO around age 35, as there is a 4% risk of ovarian cancer being discovered clinically or at the time of RRSO by age 40.10 BRCA2 carriers may choose to delay surgery into their 40s due to their lower risk of ovarian cancer, but this could diminish the protection against breast cancer that is afforded by RRSO. If a mutation carrier, particularly a BRCA1 carrier, chooses to pursue fertility into her 40s, then she should be counseled that she is at considerable risk of developing a life-threatening cancer that is largely preventable.
Several studies have provided evidence of the efficacy of RRSO. In one early study of BRCA1/2 carriers, RRSO reduced the rate of breast and ovarian cancer by 75% over several years of follow-up.40 A separate study in 2002 examined outcome in 551 BRCA1/2 carriers from various registries.41 Among 259 women who had undergone RRSO, 6 (2.3%) were found to have stage I ovarian cancer at the time of the procedure and 2 (0.8%) subsequently developed serous peritoneal carcinoma. Among the controls, 58 (20%) women developed ovarian cancer after a mean follow-up of 8.8 years. With the exclusion of the six women whose cancers were diagnosed at surgery, RRSO reduced ovarian cancer risk by 96%. More recently, in 2014, an international registry study of over 5,783 subjects with median follow-up of 5.6 years found that RRSO reduced ovarian, tubal, and peritoneal cancer risk by 80%.36There was an estimated lifetime risk of primary peritoneal cancer after RRSO of about 4% for BRCA1 carriers and 2% for BRCA2 carriers.36 The risk of death from all causes was reduced by 77%. A prospective cohort study noted that RRSO was associated with reduction in breast cancer–specific (hazard ratio [HR] = 0.44; 95% confidence interval [CI] = 0.26 to 0.76), ovarian cancer–specific (HR = 0.21; 95% CI = 0.06 to 0.80), and all-cause mortality (HR = 0.40; 95% CI = 0.26 to 0.61).10
Removal of the ovaries, as internal organs, usually has little effect on body image and self-esteem, and most BRCA1/2 mutation carriers elect to undergo RRSO. Insurance payers will almost always pay for RRSO in proven mutation carriers.
RRSO can be performed laparoscopically in most women, with discharge to home the same day. If a laparoscopic approach is problematic due to obesity or adhesions, the surgery can be performed through a small lower abdominal incision. Morbidity including bleeding, infection, and damage to the urinary or gastrointestinal tracts can occur, but the incidence of serious complications is very low. As the fallopian tubes and ovaries are small discrete organs, they are relatively easy to remove completely. Attention should be paid to transecting the ovarian artery and vein proximal to the ovary and tube so that remnants are not left behind. This involves opening the pelvic sidewall peritoneum, visualizing the ureter, and then isolating the ovarian blood supply. If there are adhesions between the adnexa and adjacent structures, careful dissection should be performed to ensure complete removal of the ovaries and fallopian tubes. If the uterus is not removed, care should be taken to remove the entire fallopian tube. A small portion of the tube inevitably will be left in the cornu of the uterus, but the risk of fallopian tube cancer developing in such remnants appears to be negligible.
Though there is not strong evidence that BRCA1/2 mutations increase uterine cancer risk, many women elect to have the uterus removed as part of the surgical procedure because they have completed their family or have other gynecologic indications. Although the addition of a hysterectomy may increase operative time, blood loss, surgical complications, and hospital stay, it usually can be performed laparoscopically and serious adverse outcomes are infrequent. Furthermore, the likelihood of future exposure to tamoxifen in the context of breast cancer prevention or treatment, which increases endometrial cancer risk two- to three-fold, also argues for concomitant hysterectomy. Women who receive hormone replacement therapy after surgery will require a progestin along with estrogen to protect against the development of endometrial cancer if the uterus is not removed.
In younger women, surgical menopause after RRSO is associated with vasomotor symptoms, vaginal atrophy, decreased libido, and an accelerated onset and incidence of osteoporosis and cardiovascular disease. In premenopausal women who do not have a personal history of breast cancer, estrogen replacement can be administered to ameliorate many of the deleterious effects of premature menopause. Systemic estrogen levels are lower in oophorectomized premenopausal women taking hormone replacement than if the ovaries had been left in place. The therapeutic benefit of oophorectomy in women with breast cancer has long been appreciated, and more recent studies support the contention that RRSO reduces the risk of breast cancer by about half in BRCA1/2 carriers.42 However, a meta-analysis showed that while RRSO was strongly protective against estrogen receptor–positive breast cancer (HR = 0.22), there was no protection against estrogen receptor–negative breast cancer.42 Many carriers are identified after developing early onset breast cancer, and this group represents the most difficult in which to balance the potential risks and benefits of estrogen replacement therapy.
Early stage high-grade serous cancers and in situ lesions with TP53 mutations have been identified in the fallopian tubes of some RRSO specimens (Fig. 32.3). This has led to a paradigm shift in which it is now thought that most high-grade serous cancers found in the ovary, fallopian tube, and peritoneum are derived from cells that originate in the tubal fimbria.43 The frequency of occult malignancies has varied between reports, but appears to be about 3%.43In view of this, the pelvis and peritoneal cavity should be examined carefully. Malignant cells also have been found in peritoneal cytologic specimens, and washings of the pelvis should be obtained when performing RRSO. The pathologist should be informed of the indication for surgery and serial sections of the fallopian tubes should be performed to look for the presence of early lesions. Patients found to have occult invasive high-grade serous cancers should be treated with chemotherapy after surgery. Those with in situ lesions appear to have a good outcome without chemotherapy.44
Cases of peritoneal serous carcinoma indistinguishable from ovarian cancer have been observed years after RRSO, but the origin of these cancers is unclear. Some may represent recurrences of occult ovarian or tubal cancers. In this regard, retrospective examination of the ovaries and fallopian tubes sometimes has revealed primary cancers that were not originally recognized. In contrast, some of these cancers likely arise directly from fallopian tube cells that have implanted in the peritoneum and subsequently become malignant. Patients who undergo RRSO should be made aware of their residual risk of peritoneal cancer, but there is no evidence that continued surveillance using CA125 and/or ultrasound is beneficial.
HEREDITARY ENDOMETRIAL CANCER (LYNCH SYNDROME)
Although Lynch syndrome (LS, also known as hereditary nonpolyposis CRC syndrome) typically manifests as familial clustering of early onset CRC, there is also an increased incidence of several other types of cancers—most notably endometrial cancer in women.45 About 3% of endometrial cancers are attributable to inherited mutations in the DNA mismatch repair (MMR) genes that cause LS. Most often, MSH2and MLH1 are implicated, but mutations in MSH6 and PMS2 also occur.45 The risk of ovarian cancer is also significantly increased in LS, but to a lesser degree than in BRCA1/2 mutation carriers, and accounts for only about 1% of all ovarian cancers.
Cells in which one of the LS genes have been inactivated exhibit a phenomenon called microsatellite instability (MSI).46 This occurs as DNA mismatches cause shortening or lengthening of repetitive DNA sequences and these mismatches go unrepaired. This results in generation of alleles in the cancer that contain a greater or lesser number of repeats than are present in normal cells from that individual. MSI occurs in most LS-associated colorectal and endometrial cancers.46 However, MSI is found in about 20% of sporadic cancers that arise in these organs, and in most cases is caused by silencing of the MLH1gene due to promoter hypermethylation. Screening strategies for identification of MMR gene alterations in families with LS-associated cancers include analysis of tumor tissue for MSI and/or loss of DNA MMR gene expression using immunohistochemistry (IHC).46 In cancers with MSI or loss of expression of one of the MMR genes, or in families with pedigrees suggestive of LS, these genes can be sequenced to identify disease-causing mutations, most of which cause truncated protein products.47 Although it has been suggested that it may be cost-effective to do these tests on all endometrial cancers, this approach has not been widely adopted.47
The risk of a woman who carries a LS mutation developing endometrial cancer ranges from 20% to 60% in various reports.45,48 The risk of ovarian cancer is increased to about 5% to 12%. Whereas the mean age of women with sporadic endometrial cancers is in the early 60s, cancers that arise in association with LS are often diagnosed before menopause, with the average age in the 40s. The clinical features of these endometrial cancers are similar to those of most sporadic cases (well-differentiated, endometrioid histology, early stage), and survival is about 90%. The mean age of onset of ovarian cancer in LS is in the early 40s, and the clinical features of these cancers are generally more favorable than in sporadic cases. They usually are identified at an early stage, are well- or moderately differentiated, have favorable survival, and some occur in the setting of a synchronous endometrial cancer.
Recommendations for screening and risk-reducing surgery in LS are better established for CRC than for extracolonic malignancies.49 Transvaginal ultrasound has been proposed as a screening test for endometrial cancer (and ovarian cancer), but its efficacy is unproven.50 Endometrial biopsy is the most sensitive means of diagnosing endometrial cancer, and it has been suggested that this should be employed periodically beginning around age 30 to 35. However, there are no published studies demonstrating that this approach prevents endometrial cancer deaths compared to simply performing a biopsy if abnormal uterine bleeding occurs.
Most experts believe that risk-reducing hysterectomy has a role in the management of some women with LS because of the high incidence of endometrial cancer. The risk of endometrial cancer is low during the prime reproductive years, and the uterus does not serve a vital function once childbearing has been completed. In view of the increased risk of ovarian cancer in LS, concomitant bilateral salpingo-oophorectomy should also be considered. One study demonstrated that there were no cases of endometrial or ovarian cancer in 61 LS carriers who underwent risk-reducing hysterectomy and bilateral salpingo-oophorectomy, while endometrial cancer occurred in 33% and ovarian cancer in 5% who retained their uterus and ovaries.51 Despite the low risk of death from gynecologic cancers in LS, cost-effectiveness analyses of various approaches suggest that risk-reducing hysterectomy and salpingo-oophorectomy leads to both the lowest cost and the greatest increase in quality-adjusted life-years.52 Estrogen replacement after removal of the ovaries in premenopausal women with LS is not contraindicated, as there is no evidence that this adversely affects the incidence of other cancers.
Many women with LS elect to undergo risk-reducing colectomy, which provides an opportunity to perform concomitant hysterectomy. Hysterectomy in concert with colectomy, either via laparoscopy or laparotomy, does not greatly increase operative time or surgical complications. If an endometrial biopsy has not been performed preoperatively, an intraoperative inspection of the uterine cavity and possibly frozen section should be performed to exclude the presence of cancer. If cancer is found in the uterus, surgical staging—including sampling of the regional lymph nodes—should be considered in addition to hysterectomy.53 It is also appropriate to discuss risk-reducing hysterectomy with LS carriers who do not elect to undergo prophylactic colectomy. The operative approach (vaginal versus laparotomy versus laparoscopy) can be determined based on the presence or absence of uterine pathology (e.g., myomas), whether the patient has had prior abdominal surgery, and whether the ovaries are also to be removed.
GYNECOLOGIC CANCER RISK IN VERY RARE HEREDITARY CANCER SYNDROMES
Several very rare hereditary cancer syndromes also increase the risk of gynecologic cancers, and some of these women could potentially benefit from risk-reducing surgery to remove the ovaries and/or uterus. Peutz-Jeghers syndrome is characterized by intestinal polyps and an increased risk of colorectal and breast cancers. This rare syndrome is due to inherited mutations in the STK11 gene. Affected women also have an increased risk of ovarian sex cord–stromal tumors with annular tubules and adenoma malignum of the cervix. Li-Fraumeni syndrome is caused by inherited mutations in the TP53 gene, and carriers are predisposed to a number of types of cancers including sarcomas and breast cancer. The risk of ovarian cancer is increased as well, but is not a major cause of cancer in these families. Cowden syndrome is due to germline PTEN mutations and increases the risk of several malignancies including breast, thyroid, mucocutaneous, and endometrial cancers. Finally, small cell carcinoma of the ovary, hypercalcemic type, is due to mutations in the SMARCA4 gene. These highly lethal ovarian cancers occur at a very young age (median 24 years) and present difficult challenges related to timing of RRSO. There are no well-accepted evidence-based guidelines for early detection and prevention of gynecologic cancers in these very rare hereditary cancer syndromes. An awareness of the risk and natural history of gynecologic cancers in these families provides a basis for counseling individual patients.
MULTIPLE ENDOCRINE NEOPLASIA TYPE 2
Gene Carriers
The MEN type 2 syndromes include MEN 2A, MEN 2B, and familial (non-MEN) medullary thyroid carcinoma (FMTC).54–56 These are autosomal dominant inherited syndromes caused by germline mutations in the RET proto-oncogene. Their hallmark is the development of multifocal bilateral medullary thyroid carcinoma (MTC) associated with C-cell hyperplasia. MTCs arise from the thyroid C-cells, also called parafollicular cells. C-cells secrete the hormone calcitonin, a specific tumor marker for MTC. A slow-growing tumor in most cases, MTC causes significant morbidity and death in patients with uncontrolled local or metastatic spread. Large tumor burden is associated with diarrhea and flushing. In the MEN 2 syndromes, there is almost complete penetrance of MTC. Other features are variably expressed, with incomplete penetrance (summarized in Table 32.2).
In MEN 2A, all patients develop MTC. Approximately 42% of affected patients also develop pheochromocytomas, associated with adrenal medullary hyperplasia. Hyperparathyroidism develops in 10% to 35%. Cutaneous lichen amyloidosis and Hirschsprung’s disease are infrequently associated with MEN 2A.57–60
MEN 2B appears to be the most aggressive form of hereditary MTC. In MEN 2B, MTC develops in all patients at a very young age (infancy). All affected individuals develop neural gangliomas, particularly in the mucosa of the digestive tract, conjunctiva, lips, and tongue; 40% to 50% develop pheochromocytomas. Patients with MEN 2B may also have megacolon, skeletal abnormalities, and markedly enlarged peripheral nerves. They do not develop hyperparathyroidism.
FMTC is characterized by development of MTC in the absence of any other endocrinopathies. MTC in these patients has a more indolent clinical course. Some individuals with FMTC may never manifest clinical evidence (i.e., symptoms or a lump in the neck), although biochemical testing and histologic evaluation of the thyroid demonstrates MTC.55,56
RET Genotype-Phenotype Correlations
Mutations in the RET proto-oncogene are responsible for MEN 2A, MEN 2B, and FMTC.61–64 This gene encodes a transmembrane tyrosine kinase protein.57,65 The mutations that cause the MEN 2 syndromes are activating gain-of-function mutations affecting constitutive activation of the protein. This is unusual among hereditary cancer syndromes, which are usually caused by loss-of-function mutations in the predisposition gene (e.g., familial polyposis, BRCA1 and 2, von Hippel-Lindau, and MEN 1). More than 30 missense mutations have been described in patients affected by the MEN 2 syndromes (Fig. 32.4).
There is a relationship between the type of inherited RET mutation and presentation of MTC. The most virulent form is seen in patients with MEN 2B. These patients most commonly have a germline mutation in codon 918 of RET (ATG->ACG), although other mutations have been described (codon 883 and 922). As noted previously, MTC in MEN 2B has an extremely early age of onset (infancy). Despite its distinctive clinical appearance and associated gastrointestinal difficulties, the disease is often not detected until the patient develops a neck mass. Metastatic spread is usually present at the time of initial treatment, and calcitonin levels often remain elevated postoperatively.
MTC has a variable course in patients with MEN 2A, similar to that of sporadic MTC. Codon 634 and 618 mutations are the most common RET mutations associated with MEN 2A, although mutations at other codons are also observed (see Fig. 32.4). Some patients do extremely well for many years, even with distant metastases, while others develop inanition, symptomatic liver, lung or skeletal metastases, as well as disabling diarrhea. Recurrence in the central neck, with invasion of the airway or great vessels, may cause death.
In patients with FMTC, MTC is usually indolent. These individuals most commonly have mutations of codons 609, 611, 618, 620, 768, 804, or 891, although mutations of other codons have been identified (see Fig. 32.4). Many patients with FMTC are cured by thyroidectomy alone, and even those with persistent elevation of calcitonin levels do well for many years. Occasionally, patients with FMTC survive into the seventh or eighth decade without clinical signs of disease, although pathologic examination of the thyroid will reveal MTC or C-cell hyperplasia.66
Risk-Reducing Thyroidectomy in RET Mutation Carriers
Genetic counseling and informed consent should be obtained prior to genetic testing. Specific issues that should be covered in genetic counseling sessions include explaining the patterns of heritability, likelihood of expression of different tumors, their prevention and treatment, insurability, nonpaternity, survivor guilt, and others.
It has been shown that RET mutation carriers may harbor foci of MTC in the thyroid gland, even when calcitonin levels are normal.67 While the age of onset and rate of disease progression may differ, the lifetime penetrance of MTC is near 100% in carriers of RET mutations associated with MEN 2 syndromes. At-risk individuals who are found to have inherited a RET gene mutation are therefore candidates for thyroidectomy, regardless of their plasma calcitonin levels.
The best option for prevention of MTC in RET mutation carriers is complete surgical resection prior to malignant transformation. Prophylactic thyroidectomy prior to the development of MTC is the goal in these patients. A number of studies have demonstrated improved biochemical cure rates and/or decreased recurrence rates from early thyroidectomy, performed after positive screening by calcitonin testing or RET mutation testing.68–70
MEN 2B mutations are the highest risk level, designated level III (see Fig. 32.4).55,71 Patients with MEN 2B have the most aggressive form of MTC, with invasive disease reported in patients <1 year of age. These patients should have preventative surgery early in the first year of life, if possible. Identification and preservation of parathyroid glands can be extremely difficult in these infants, due to their small size, translucent appearance, and the presence of exuberant thymic and perithyroidal nodal tissue. These procedures should be performed by surgeons experienced in parathyroid and/or pediatric thyroid operations.
Patients with MEN 2A with mutations in codons 634, 620, 618, and 611 are also considered high risk (level II).55,71 Patients with level II mutations should undergo a total thyroidectomy at 5 to 6 years of age. There is evidence that the risk of lymph node metastasis is very low in patients with MEN 2A under the age of 8, with normal calcitonin levels. Central lymph node dissection is associated with higher risk of hypoparathyroidism, and recurrent laryngeal nerve injury and should be reserved for patients with elevated calcitonin levels.
A larger subset of RET mutations, associated with MEN 2A and/or FMTC, is considered the lowest risk (level I).55,71 These include mutations at codons 768, 790, 791, 804, and 891. For patients with low-risk level I mutations, total thyroidectomy is recommended before age 5 to 10 years. This decision, however, regarding ideal age at preventative thyroidectomy in low-risk mutation carriers, is currently being reviewed, and may be driven by additional clinical data such as the basal or stimulated serum calcitonin level.72,73 There are no guidelines at present that address the issue of timing of surgery based on calcitonin level, and at present, pentagastrin (the primary calcitonin secretagogue used in testing) is not available in the United States. It is anticipated that within a decade, there will be enough published data to direct timing of interventions based upon this information. As with the level II mutations, the need for central lymph node dissection should be guided by calcitonin levels and clinical features of the patient and kindred.
Until recently, some groups recommended total thyroidectomy with central neck lymph node dissection and total parathyroidectomy with autotransplantation for all RET mutation carriers. Recent studies and personal experience, however, have demonstrated an extremely low likelihood of nodal metastases in patients with MEN 2A or FMTC younger than 8 years of age, and in patients with a normal calcitonin level.70 Our current strategy is to leave the parathyroid in situ in these patients, if possible.74 Often, however, the desired complete removal of thyroid tissue results in compromise of parathyroid blood supply. In these situations, autotransplantation of devascularized parathyroid is required. We routinely remove and autotransplant the parathyroid if a central node dissection is done. In parathyroid autotransplantation, parathyroid glands are sliced into 1 mm × 3 mm fragments and autotransplanted into individual muscle pockets in the muscle of the nondominant forearm in patients with MEN 2A, or in the sternocleidomastoid muscle in patients with FMTC or MEN 2B. Patients are maintained on calcium and vitamin D supplementation for 4 to 8 weeks postoperatively.
In a recent series of thyroidectomies performed in 50 individuals with MEN 2A (identified by genetic screening), total thyroidectomy and central node dissection with parathyroidectomy and parathyroid autografting were performed in all patients (Fig. 32.5).70 All autografts functioned, but three patients required supplemental calcium. The percentage of individuals requiring calcium supplementation following parathyroidectomy with parathyroid autografting reportedly ranges from 0% to 18%. Parathyroidectomy should be performed in all patients showing gross parathyroid enlargement or biochemical evidence of parathyroid disease at time of surgery. The operating surgeon should have expertise in preservation of parathyroid function. It is important that the surgeon performing an operative procedure for MTC be familiar with the techniques described here. If not, the patient should be referred to a center where these procedures are routinely performed.
Some patients with MEN 2 will be found to have elevated calcitonin levels prior to thyroidectomy. This is usually associated with medullary thyroid carcinoma or C-cell hyperplasia in the gland, and may be associated with lymph node metastases. Much has been written about the correlation between preoperative calcitonin levels and extent of nodal involvement. It has been suggested that preoperative calcitonin level may guide the extent of node dissection. In a study of 300 European patients with MTC, node metastases were not identified when the preoperative basal calcitonin level was <20 pg/ml.75 Involvement of nodal groups was correlated with basal calcitonin level as follows: ipsilateral central and lateral neck nodes (basal calcitonin >20 pg/ml), contralateral central nodes (basal calcitonin >50 pg/ml), contralateral lateral neck nodes (basal calcitonin >200 pg/ml), and mediastinal nodes (basal calcitonin >500 pg/ml). Based upon these findings, this group (who also wrote the European guidelines) recommends thyroidectomy only if basal calcitonin is <20 pg/ml, ipsilateral central and lateral neck dissection if the calcitonin is 20 to 50 pg/ml, and contralateral central neck dissection if the basal calcitonin is 50 to 200 pg/ml, with the addition of contralateral lateral neck dissection if the calcitonin is 200 to 500 pg/ml. Most experts agree that sternotomy with mediastinal neck dissection should be reserved for patients with image evidence of mediastinal disease. In contrast, most North American surgeons rely heavily upon preoperative ultrasound imaging to map the extent of nodal involvement and determine extent of surgery based upon calcitonin and imaging results.55,74,76
Follow-up
Following thyroidectomy, thyroid hormone replacement is required for life. Patients may need several weeks of oral calcium and vitamin D until parathyroid function recovers. Intermittent calcitonin testing may be done to monitor for persistent or recurrent MTC. The importance of regular monitoring of patients’ compliance with thyroid medication following thyroidectomy should not be underestimated. Children and teenagers are frequently noncompliant, and this can be determined by routine measurement of thyroid-stimulating hormone levels. Continued noncompliance can result in growth problems. Occasionally, local human services agencies may need to be involved in particularly difficult cases.
The term “biochemical cure” is used to refer to patients with normal calcitonin levels after surgery for MTC. Complete postoperative normalization of calcitonin has been associated with decreased long-term risk of MTC recurrence, though the evidence is less clear for a survival benefit. A persistent or recurrent elevation in calcitonin indicates residual or recurrent MTC and warrants additional investigation by imaging. However, as most MTC has a fairly indolent course, patients with biochemical evidence of recurrent disease may not have corollary imaging findings for some time.
Conclusions
Identification of RET gene mutations in individuals at risk for developing hereditary forms of MTC has simplified management, expanding the scope of indications for surgical intervention. Patients who carry this mutation can be offered operative treatment at a very young age, hopefully before the cancer has developed or spread, and those identified as not having the mutation are spared further genetic and biochemical screening. This achievement marks a new paradigm in surgery: the indication that an operation be performed based on the results of a genetic test. As in the decision to perform any surgical procedure, meticulous preparation and detailed discussion with patient and family must precede the final recommendation. It is also important that the patient and family be involved in preoperative discussions with genetic counselors. Postoperative follow-up for compliance with thyroid medication is important, especially in children and teenagers who are still growing and developing into adults.
FAMILIAL ADENOMATOUS POLYPOSIS, MYH-ASSOCIATED POLUPOSIS, AND LYNCH SYNDROME
Inherited CRC syndromes with multiple adenomatous polyps include FAP, MYH-associated polyposis (MAP), and LS. In some cases, the diagnosis is suspected because of a striking family history of CRC, while in others, suspicion arises from a very young onset of CRC or florid polyposis.
Although adenomatous polyp burden and family history may suggest one syndrome over another, an initial negative genetic test result should be followed by further evaluation for other syndromes. For example, in clinical practice, a negative adenomatous polyposis coli (APC) gene test in a patient with a suspected CRC syndrome is followed by reflex testing for MAP and LS, as shown in Figure 32.6.
FAP is an autosomal dominant syndrome that accounts for <1% of the annual CRC burden, is caused by mutations in the tumor-suppressor APC gene. It is characterized by the presence of ≥100 adenomatous polyps in the colorectum, nearly 100% penetrance, and an inevitable risk of CRC if prophylactic colectomy is not performed.8,77 Patients with a less severe form known as attenuated FAP (AFAP) usually present with <100 colorectal adenomas that tend to be proximally located. MAP is an autosomal recessive syndrome that often presents phenotypically as attenuated polyposis. While an estimated 2% of the general population are monoallelic carriers of a mutated base-excision-repair MUTYH (MYH) gene, biallelic germline mutations may account for 9% to 18% of patients with FAP or AFAP phenotypes who have no demonstrable APC mutation.78–80
LS accounts for 1% to 4% of all newly diagnosed CRC and is attributable to a germline mutation in one of the DNA MMR genes (MLH1, MSH2, MSH6, and PMS2).81–83 Epigenetic silencing of the MSH2gene via a 3′-end deletion in EPCAM (TACSTD1), a neighbor of MSH2 that plays a role in cell adhesion, also accounts for 20% to 25% of all suspected MSH2 cases and 1% to 6% of LS cases overall.84–86 LS is characterized by early age-of-onset CRC, predominance of lesions proximal to the splenic flexure, an increased rate of metachronous CRC, and a unique spectrum of benign and malignant extracolonic tumors. Lifetime risk of CRC in patients with LS may be as high as 80%.83,87 MSI reflects a deficiency in DNA repair secondary to MMR gene mutation and is a hallmark feature of LS-associated tumors.
Variability in penetrance, phenotypic expression, and certainty of disease development mandate distinctly different surgical approaches in these three syndromes, including the type and timing of risk-reducing colon and rectal surgery.88
Familial Adenomatous Polyposis
Surveillance of at-risk family members should begin around age 10 to 15 years with an annual colonoscopy or flexible sigmoidoscopy.89 At-risk individuals who belong to families with an AFAP phenotype should undergo colonoscopic screening every 2 to 3 years starting in their late teens. Informative genetic testing is possible in families with a demonstrated APC mutation, and mutations are detected in most pedigrees. However, approximately 25% of patients with FAP will have a de novo APC mutation.87 Severity of polyposis should be established during colonoscopy, as the timing of surgery and the risk of developing colorectal is dependent on the extent of polyp burden. Patients with mild polyposis and a correspondingly lower CRC risk can undergo surgery in their late teens. Patients with severe polyposis, a high degree of dysplasia, multiple adenomas >5 mm in size, and symptoms (bleeding, persistent diarrhea, anemia, failure to thrive, psychosocial stress, etc.) should undergo risk-reducing colorectal surgery as soon as is practical after diagnosis.90,91 However, in carefully selected, fully asymptomatic patients who have small adenomas but a strong family history of aggressive abdominal desmoid disease, consideration can be given to delaying prophylactic colectomy, as the risk of desmoid-related complication may be greater than the risk of CRC development.
The three current surgical options for patients with FAP are total proctocolectomy (TPC) with permanent ileostomy, total colectomy with ileorectal anastomosis (IRA), and proctocolectomy with ileal pouch-anal anastomosis (IPAA). IPAA can be a double-stapled, end-of-pouch-to-anus anastomosis, which may leave behind approximately 1 cm of anal transition zone. An alternative approach, which is preferred when there is carpeting of the anal transition zone with adenomas, is to perform a mucosal stripping of the anal transition zone down to the dentate line followed by a hand-sewn per anal anastomosis of pouch to the dentate line. Selection of the optimal procedure for an individual patient is based on several factors, including characteristics of the FAP syndrome within the patient and family, differences in likely postoperative functional outcome, preoperative anal sphincter status, and patient preference.8
TPC with permanent ileostomy, although rarely chosen as a primary procedure, is used in patients with invasive cancer involving the sphincters or levator complex, or patients for whom an IPAA is not technically feasible (secondary to desmoid disease and foreshortening of the small bowel mesentery, making it surgically impossible to bring the ileal pouch to the anus) nor likely to lead to good function such as massive obesity or weak anal sphincters. However, TPC is occasionally chosen as a primary procedure by patients who perceive that their lifestyle would be compromised by the frequent bowel movements (five to six per day) sometimes associated with the IPAA procedure.
In addition to these issues, the key in deciding between an IPAA and an IRA is based primarily on the risk of rectal cancer development if the rectum is left in situ. The risk of rectal cancer following IRA may range from 3% to 10% at 10 years, while the risk for a secondary proctectomy for uncontrolled rectal polyposis ranges from 10% to 61% at 20 years following initial colectomy with IRA.92–94 The magnitude of risk in an individual patient is, however, related to the overall extent of colorectal polyposis. IRA may be considered for patients with <1,000 colorectal polyps (including those with attenuated FAP) and <20 rectal adenomas, as these individuals have a relatively low risk of developing rectal cancer.88,93 Patients with severe rectal (>20 adenomas) or colonic (>1,000 adenomas) polyposis, an adenoma >3 cm, or an adenoma with severe dysplasia should ideally undergo a risk-reducing procedure that will include a proctectomy.90,91,93
The risk of secondary rectal excision, due to uncontrollable rectal polyposis or rectal cancer, may be estimated by identifying the specific location of the causative APC mutation. Patients with mutations located between codons 1250 and 1464 have been shown to have a six-fold increased risk of developing rectal cancer, compared to those with mutations prior to codon 1250 or after codon 1464 (mean number of rectal polyps 42 versus 22, respectively).8,92Although the use of the genotype-phenotype relationship to guide patient management may be appealing,92 it is important to recognize the variability of phenotypic expression that exists even among members of the same family. This suggests that at the current time, the choice between an IRA and an IPAA should be based primarily on clinical (rather than genetic) grounds.90
The risk of polyp and cancer development following primary surgery is not limited to patients undergoing IRA. In patients undergoing IPAA, neoplasia may occur at the site of ileal pouch anastomosis; the frequency appears to be greater after stapled anastomosis (28% to 31%) than after mucosectomy and hand-sewn anastomosis (10% to 14%).95 In the case of neoplasia developing at the anal transition zone after a stapled anastomosis, transanal mucosectomy may be performed, followed by advancement of the pouch to the dentate line. Of additional concern is the development of adenomatous polyps in the ileal pouch, which occurs in approximately 45% of patients by 10-year follow-up.96 Consequently, depending on polyp burden, lifetime endoscopic surveillance of the rectal remnant (after IRA) every 6 to 12 months or the ileal pouch (after IPAA) every 1 to 3 years is required following either procedure.89
Another important consideration in choosing between IPAA and IRA is postoperative bowel function and quality of life. Some studies have associated IPAA with higher frequency of both daytime and nocturnal bowel movements, higher incidence of passive incontinence and incidental soiling, and greater postoperative morbidity.97 However, long-term follow-up demonstrates a comparable quality of life following IPAA for FAP relative to the patient’s preoperative baseline.98 Therefore, although the choice of procedure must be carefully individualized, because of the risk of rectal cancer associated with IRA, the authors favor IPAA for most patients with FAP whenever feasible. However, an IRA should be considered in specific circumstances, such as when there is mild rectal polyposis (as in AFAP), or a young patient with rectal sparing who is not interested in undergoing the multiple procedures that accompany an IPAA and diverting loop ileostomy, or a young woman interested in having children and trying to avoid the decreased fecundity associated with an IPAA procedure.99 The use of minimally invasive techniques such as laparoscopy may reduce the risk of infertility associated with IPAA.100,101 Though a diverting loop ileostomy should be performed in all IPAA procedures, it is not always feasible due to a number of anatomic factors such as body habitus.
Endoscopic surveillance of the rectal segment at 6- to 12-month intervals after the index surgery is recommended, with subsequent surveillance frequencies dependent on the number and size of adenomas observed.89 Although small (<5 mm) scattered adenomas can be safely observed or removed with biopsy forceps, polyps >5 mm should be removed by snare. However, repeated fulguration and polypectomy over many years can lead to difficulty with subsequent polypectomy, reduced rectal compliance, and difficulty identifying flat cancers in the background of scar tissue. The development of severe dysplasia and/or villous adenomas not amenable to endoscopic removal is indication for proctectomy.
Long-Term Considerations from Extracolonic Manifestations
Despite the reduced risk of CRC-related death following prophylactic colectomy, patients with FAP are still at increased risk of mortality from both rectal cancer and other causes relative to the general population. The three main causes of death following IRA are progression of desmoid disease, stomach and duodenal cancer, and perioperative mortality. Additional FAP-related extraintestinal manifestations include epidermoid cysts, supernumerary teeth, osteomas of the jaw and/or skull, congenital hypertrophy of the retinal pigment epithelium, cancers of the hepatopancreatobiliary tract and genitourinary tract, and thyroid cancer.102–104
Desmoids
Desmoids may occur in 10% to 25% of patients with FAP.105,106 Unlike those found in the general population, FAP-associated desmoids tend to be intra-abdominal and arise following abdominal surgery.106,107Although conflicting reports exist, it appears that female patients, those with extracolonic manifestations of FAP, a positive family history of desmoids, and APC mutations located at 3′ of codon 1440 are at increased risk of developing desmoids.106,108,109These tumors often involve the small bowel mesentery as well as the retroperitoneum and are often life-threatening due to invasion or compression of adjacent viscera. Further, recurrence and morbidity rates are high following attempted resection, with recurrent disease often more aggressive than the initial desmoid. Estimated 5-year overall survival for patients with intra-abdominal desmoids causing severe symptoms such as significant pain and septic fistula/abscess, diameter >20 cm or rapidly growing, and/or need for parenteral nutrition is only 53%.107 Therefore, desmoid resection is evaluated on an individualized case-by-case basis with surgery reserved for highly select cases.
Desmoids that involve the small bowel mesentery may preclude the formation of an IPAA secondary to foreshortening of the small bowel mesentery, especially in patients undergoing proctectomy after an initial IRA.110 Surgery for intra-abdominal and abdominal wall desmoids should be reserved for limited disease where the likelihood of clear margins is high.
In symptomatic cases where resection of an intra-abdominal desmoid may not be feasible, intestinal bypass or ureteral stenting may be necessary to alleviate bowel or urinary obstruction secondary to mass effect. In addition to surgical intervention, several medical options with variable efficacy are available for the management of desmoid disease and include nonsteroidal anti-inflammatory drugs (e.g., sulindac), selective estrogen receptor modulators (e.g., tamoxifen), immunomodulators (e.g., imatinib, sorafenib, interferon), doxorubin-based cytotoxic chemotherapy, and radiation.
MYH-Associated Polyposis
MAP should be suspected in patients with >10 colorectal adenomas, a weak history of CRC, and no family history of FAP. The diagnosis is confirmed by MUTYH (MYH) gene testing.80,88
Depending on the polyp burden, the management of the colon and rectum of a patient with a biallelic MYH mutation can be endoscopic or surgical. If the polyp burden is limited and an endoscopic approach is pursued, colonoscopy should be performed every 1 to 3 years.87,89 If the polyp burden is not amenable to an endoscopic approach at the time of diagnosis, then a resection is indicated. In most cases in which surgery is deemed necessary, an IRA is sufficient. However, if rectal polyposis is severe, an IPAA may be indicated. Indications for surgery following an endoscopic surveillance program include increasing polyp size or number, or worsening histology.
Extracolonic manifestations of MAP are similar to FAP and include osteomas, desmoids, congenital hypertrophy of the retinal pigment epithelium, as well as cancers of the thyroid, ovary, bladder, sebaceous gland, and breast. In addition, patients with MAP are also at a 4% lifetime risk of developing duodenal cancer and require upper endoscopies every 1 to 3 years beginning as early as ages 18 to 20 years and starting no later than ages 30 to 35 years.87,89,111
Lynch Syndrome
Due to the discordance associated with the term hereditary nonpolyposis colorectal cancer, the use of this term has largely been abandoned with reversion back to the eponym LS, which refers to individuals with a predisposition to CRC and other malignancies as a result of a germline MMR mutation.112 Overall, CRC occurs in up to 80% of patients with LS by their mid-40s.8,82 Endometrial cancer occurs in 40% to 60%, gastric cancer in 11% to 19%, urinary tract cancer in 5% to 18%, and ovarian cancer in 9% to 15% of affected individuals.8,82,87
The Amsterdam criteria and revised Bethesda guidelines113 (Table 32.3) are used in clinical practice to identify patients at risk for LS who require further genetic evaluation. The Amsterdam criteria, which led to the identification of the LS-causing MMR gene mutations require that there be:
Three relatives (one a first-degree relative of the other two) with colorectal, endometrial, stomach, ovary, small bowel, ureteral/renal pelvis, brain, hepatobiliary, and/or sebaceous cancer;
In two or more successive generations;
With at least one case of cancer diagnosed before the age of 50;
And that FAP as a diagnosis is excluded.114
Though the Amsterdam criteria can be used clinically to identify potential patients with LS, using it alone will result in identification of only 42% of LS mutation carriers.115 Families meeting Amsterdam criteria but lacking an MMR mutation are referred to as having “familial colorectal cancer type X” and appear to have a lower incidence of colorectal and extracolonic cancers than those with a LS germline MMR mutation (see Fig. 32.6). Of note, they have an increased incidence of left-sided and nonmucinous microsatellite stable tumors.77,88
Patients with CRC who belong to pedigrees suspicious for LS should be offered screening by IHC for loss of MMR protein expression or by MSI analysis. As the sensitivity of IHC testing for loss of MMR protein expression is comparable to MSI testing, either approach can be pursued.112 However, IHC testing is less expensive and can also identify a specific MMR protein loss, which can help target subsequent germline testing. Routine IHC testing for loss of MMR protein in individuals younger than 50 years at the time of CRC diagnosis is feasible and has led to the identification of patients with LS who might otherwise have been missed.116,117 Patients with MSI-high tumors should undergo testing for germline MMR mutations in MSH2, MLH1, MSH6, and PMS2. Reflex IHC and/or MSI testing on all newly diagnosed CRC has been advocated by some expert groups and has been successfully implemented at some institutions.83,112,118 However, a majority of cancer programs nationwide currently do not have a protocol for reflex testing for LS, citing lack of institutional protocols as well as fear of nonreimbursement.119 As such, a unified move toward universal testing remains some time away. In families for which tumor tissue is not available, initial germline testing may be considered though the financial burden is not insignificant, with the cost of finding a single LS carrier measuring approximately $58,000 (compared to the $5,000 spent in finding a single LS carrier using IHC screening).120 As in FAP, a mutation in an affected individual must be established for testing in at-risk individuals to be conclusive.
In lieu of universal testing, several predictive models such as the MMRpredict, MMRpro, and PREMM1,2,6 have been devised in order to assess an individual’s likelihood of harboring LS.115,121,122 These models quantify an individual’s risk for carrying an MLH1, MSH2, or MSH6 germline mutation by using clinical characteristics such as age at onset of CRC and/or other LS-associated cancers, location of CRC, family history, history of synchronous or metachronous CRC, among others. A study of these predictive models demonstrated that they all performed better than the revised Bethesda guidelines in terms of identifying patients with germline mutations for LS.123 The MMRpredict model appeared to have to be the best predictor, with a sensitivity and specificity for LS of 94% and 91%, respectively. Other validation studies, however, have not demonstrated the superiority of MMRpredict compared to the other aforementioned models.124,125 It appears that the use of clinical characteristics in combination with MSI or MMR protein expression status in predictive models may potentially improve our ability to establish LS diagnoses in patients with CRC. However, the practicality and applicability of these tools in a clinical setting requires further assessment.
Although development of CRC in LS is not a certainty, the 80% lifetime risk, the 16% to 30% risk of metachronous CRC, and the possibly accelerated adenoma-to-carcinoma sequence mandate consideration of prophylactic surgical options.82,87,126–129 Patients with LS who have a CRC or more than one advanced adenoma should be offered the options of prophylactic total colectomy with IRA or segmental colectomy with annual postoperative surveillance colonoscopy. Careful surveillance is also necessary after total colectomy and IRA, as the risk of high-risk adenomas and cancer in the retained rectum at a median of 104 months are 11% and 8%, respectively.126 Although there has been no study demonstrating an improved survival for patients with LS undergoing total colectomy and IRA versus segmental colectomy, mathematical models suggest a slight survival benefit for total colectomy and IRA, especially for individuals under the age of 30.130,131 In addition, because of increased rates of metachronous CRC development and the risk of multiple abdominal surgeries in those undergoing a segmental resection, a total colectomy and IRA has emerged as the procedure of choice for the index cancer, with consideration for TPC in cases where a high risk of metachronous rectal cancer can be predicted.126–128 Targeted genetic testing approaches—such as the single amplicon MSH2 A636P mutation test in Ashkenazi Jewish patients with CRC—have demonstrated how a rapid and inexpensive preoperative genetic test can help direct the extent of colon resection.132
LS mutation carriers with a normal colon and without a history of CRC may also be offered prophylactic colectomy in highly select situations. One rationale for this approach is the similarity of lifetime cancer risk between patients with APC and MMR gene mutations, and the fact that total abdominal colectomy with IRA produces less functional disturbance than the prophylactic procedure recommended for FAP (TPC with IPAA). However, an alternate strategy for these individuals is surveillance by colonoscopy, which is cost-effective and greatly reduces the rate of CRC development and overall mortality.133There is a risk of CRC development in the interval between colonoscopies, though most interval cancers tend to be early stage.134,135 As such, given that metachronous CRC may develop in as short a duration as a median of 11.3 months,136 the recommended interval for surveillance colonoscopies is now every 1 to 2 years.89 While prophylactic colectomy is not routinely recommended, it may be indicated in highly select patients for whom colonoscopic surveillance is not technically possible or in those who refuse to undergo regular surveillance. A decision analysis model suggests that prophylactic subtotal colectomy at age 25 may offer a survival benefit of 1.8 years, compared with surveillance colonoscopy. The benefit of prophylactic colectomy decreases when surgery is delayed until later in life and is negligible when performed at the time of cancer development.137 Thus, the decision between prophylactic surgery and surveillance for a gene-positive unaffected individual is based on many factors including penetrance of disease in the family, early age-of-onset in affected family members, functional and quality-of-life considerations, and likelihood of compliance with surveillance. Table 32.4 lists some of the pros and cons of a prophylactic colectomy for germline mutation carriers for LS without a history of CRC. Patients with LS and an index rectal cancer should be offered the options of TPC with IPAA or anterior proctosigmoidectomy with primary reconstruction.128,138 The rationale for TPC is the 10% to 15% associated risk of metachronous colon cancer in the remaining colon following the index rectal cancer. Choosing between the two procedures depends, in part, on the patient’s willingness to undergo intensive surveillance of the retained proximal colon, as well as issues regarding quality of life and bowel function.
REFERENCES
1. Moyer VA, US Preventive Services Task Force. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer in Women: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2014;160.
2. Robson ME, Storm CD, Weitzel J, et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 2010;28:893–901.
3. Amir E, Freedman OC, Seruga B, et al. Assessing women at high risk of breast cancer: a review of risk assessment models. J Natl Cancer Inst 2010;102:680–691.
4. Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994;266:66–71.
5. Wooster R, Neuhausen SL, Mangion J, et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 1994;265:2088–2090.
6. Lux MP, Fasching PA, Beckmann MW. Hereditary breast and ovarian cancer: review and future perspectives. J Mol Med 2006;84:16–28.
7. Shannon KM, Chittenden A. Genetic testing by cancer site: breast. Cancer J 2012;18:310–319.
8. Guillem JG, Wood WC, Moley JF, et al. ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes. J Clin Oncol 2006;24:4642–4660.
9. Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin 2007;57:75–89.
10. Domchek SM, Friebel TM, Singer CF, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 2010;304:967–975.
11. US Equal Employment Opportunity Commission. Genetic information discrimination. http://www.eeoc.gov/laws/types/genetic.cfm. Accessed January 2, 2014.
12. Society of Surgical Oncology. Position statement on prophylactic mastectomy. http://www.surgonc.org/practice-policy/practice-management/consensus-statements/position-statement-on-prophylactic-mastectomy. Accessed February 1, 2014.
13. Hartmann LC, Schaid DJ, Woods JE, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 1999;340:77–84.
14. Eldor L, Spiegel A. Breast reconstruction after bilateral prophylactic mastectomy in women at high risk for breast cancer. Breast J 2009;15:S81–S89.
15. Zakhireh J, Fowble B, Esserman LJ. Application of screening principles to the reconstructed breast. J Clin Oncol 2010;28:173–180.
16. Gabram SG, Dougherty T, Albain KS, et al. Assessing breast cancer risk and providing treatment recommendations: immediate impact of an educational session. Breast J 2009;15:S39–S45.
17. Nadauld LD, Ford JM. Molecular profiling of gastric cancer: toward personalized cancer medicine. J Clin Oncol 2013;31:838–839.
18. Bardram L, Hansen TV, Gerdes AM, et al. Prophylactic total gastrectomy in hereditary diffuse gastric cancer: identification of two novel CDH1 gene mutations-a clinical observational study. Fam Cancer 2014;13:231–242.
19. Norton JA, Ham CM, Van Dam J, et al. CDH1 truncating mutations in the E-cadherin gene: an indication for total gastrectomy to treat hereditary diffuse gastric cancer. Ann Surg 2007;245:873–879.
20. Lynch HT, Grady W, Suriano G, et al. Gastric cancer: new genetic developments. J Surg Oncol 2005;90:114–133, discussion 133.
21. Guilford P, Hopkins J, Harraway J, et al. E-cadherin germline mutations in familial gastric cancer. Nature 1998;392:402–405.
22. Kaurah P, MacMillan A, Boyd N, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA 2007;297:2360–2372.
23. Benusiglio PR, Malka D, Rouleau E, et al. CDH1 germline mutations and the hereditary diffuse gastric and lobular breast cancer syndrome: a multicentre study. J Med Genet 2013;50:486–489.
24. Gaya DR, Stuart RC, Going JJ, et al. Hereditary diffuse gastric cancer associated with E-cadherin mutation: penetrance after all. Eur J Gastroenterol Hepatol 2008;20:1249–1251.
25. Lee KH, Hwang D, Kang KY, et al. Frequent promoter methylation of CDH1 in non-neoplastic mucosa of sporadic diffuse gastric cancer. Anticancer Res 2013;33:3765–3774.
26. Oliveira C, Sousa S, Pinheiro H, et al. Quantification of epigenetic and genetic 2nd hits in CDH1 during hereditary diffuse gastric cancer syndrome progression. Gastroenterology 2009;136:2137–2148.
27. Carneiro F, Huntsman DG, Smyrk TC, et al. Model of the early development of diffuse gastric cancer in E-cadherin mutation carriers and its implications for patient screening. J Pathol 2004;203:681–687.
28. Huntsman DG, Carneiro F, Lewis FR, et al. Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations. N Engl J Med 2001;344:1904–1909.
29. Suriano G, Yew S, Ferreira P, et al. Characterization of a recurrent germ line mutation of the E-cadherin gene: implications for genetic testing and clinical management. Clin Cancer Res 2005;11:5401–5409.
30. Rogers WM, Dobo E, Norton JA, et al. Risk-reducing total gastrectomy for germline mutations in E-cadherin (CDH1): pathologic findings with clinical implications. Am J Surg Pathol 2008;32:799–809.
31. Worster E, Liu X, Richardson S, et al. The impact of prophylactic total gastrectomy on health-related quality of life: a prospective cohort study. Ann Surg 2014;260:87–93.
32. Lim YC, di Pietro M, O’Donovan M, et al. Prospective cohort study assessing outcomes of patients from families fulfilling criteria for hereditary diffuse gastric cancer undergoing endoscopic surveillance. Gastrointest Endosc 2014;80:78–87.
33. Mavaddat N, Peock S, Frost D, et al. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J Natl Cancer Inst 2013;105:812–822.
34. Risch HA, McLaughlin JR, Cole DE, et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 2001;68:700–710.
35. Struewing JP, Hartge P, Wacholder S, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 1997;336:1401–1408.
36. Finch AP, Lubinski J, Moller P, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol 2014;32:1547–1553.
37. Walsh T, Casadei S, Lee MK, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A 2011;108:18032–18037.
38. Couch FJ, Wang X, McGuffog L, et al. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk. PLoS Genet 2013;9:e1003212.
39. Schrader KA, Hurlburt J, Kalloger SE, et al. Germline BRCA1 and BRCA2 mutations in ovarian cancer: utility of a histology-based referral strategy. Obstet Gynecol 2012;120:235–240.
40. Kauff ND, Satagopan JM, Robson ME, et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2002;346:1609–1615.
41. Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002;346:1616–1622.
42. Kauff ND, Domchek SM, Friebel TM, et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol 2008;26:1331–1337.
43. Folkins AK, Jarboe EA, Roh MH, et al. Precursors to pelvic serous carcinoma and their clinical implications. Gynecol Oncol 2009;113:391–396.
44. Wethington SL, Park KJ, Soslow RA, et al. Clinical outcome of isolated serous tubal intraepithelial carcinomas (STIC). Int J Gynecol Cancer 2013;23:1603–1611.
45. Bonadona V, Bonaiti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 2011;305:2304–2310.
46. Leenen CH, van Lier MG, van Doorn HC, et al. Prospective evaluation of molecular screening for Lynch syndrome in patients with endometrial cancer ≤ 70 years. Gynecol Oncol 2012;125:414–420.
47. Resnick K, Straughn JM Jr, Backes F, et al. Lynch syndrome screening strategies among newly diagnosed endometrial cancer patients. Obstet Gynecol 2009;114:530–536.
48. Watson P, Vasen HF, Mecklin JP, et al. The risk of endometrial cancer in hereditary nonpolyposis colorectal cancer. Am J Med 1994;96:516–520.
49. Koornstra JJ, Mourits MJ, Sijmons RH, et al. Management of extracolonic tumours in patients with Lynch syndrome. Lancet Oncol 2009;10:400–408.
50. Dove-Edwin I, Boks D, Goff S, et al. The outcome of endometrial carcinoma surveillance by ultrasound scan in women at risk of hereditary nonpolyposis colorectal carcinoma and familial colorectal carcinoma. Cancer 2002;94:1708–1712.
51. Schmeler KM, Lynch HT, Chen LM, et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med 2006;354:261–269.
52. Yang KY, Caughey AB, Little SE, et al. A cost-effectiveness analysis of prophylactic surgery versus gynecologic surveillance for women from hereditary non-polyposis colorectal cancer (HNPCC) Families. Fam Cancer 2011;10:535–543.
53. Pistorius S, Kruger S, Hohl R, et al. Occult endometrial cancer and decision making for prophylactic hysterectomy in hereditary nonpolyposis colorectal cancer patients. Gynecol Oncol 2006;102:189–194.
54. Traugott AL, Moley JF. Multiple endocrine neoplasia type 2: clinical manifestations and management. Cancer Treat Res 2009;153:321–337.
55. American Thyroid Association Guidelines Task Force, Kloos RT, Eng C, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 2009;19:565–612.
56. Wells SA Jr, Pacini F, Robinson BG, et al. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab 2013;98:3149–3164.
57. Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 1996;276:1575–1579.
58. Howe JR, Norton JA, Wells SA Jr. Prevalence of pheochromocytoma and hyperparathyroidism in multiple endocrine neoplasia type 2A: results of long-term follow-up. Surgery 1993;114:1070–1077.
59. Machens A, Niccoli-Sire P, Hoegel J, et al. Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med 2003;349:1517–1525.
60. Gagel RF, Levy ML, Donovan DT, et al. Multiple endocrine neoplasia type 2A associated with cutaneous lichen amyloidosis. Ann Intern Med 1989;111:802–806.
61. Santoro M, Carlomagno F, Romano A, et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science 1995;267:381–383.
62. Mulligan LM, Ponder BA. Genetic basis of endocrine disease: multiple endocrine neoplasia type 2. J Clin Endocrinol Metab 1995;80:1989–1995.
63. Mulligan L, Kwok J, Healy C. Germ-line mutations of the RET protooncogene in multiple endocrine neoplasia type 2A (MEN 2A). Nature 1993;363:458–460.
64. Donis-Keller H, Dou S, Chi D, et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 1993;2:851–856.
65. Traugott AL, Moley JF. The RET Protooncogene. Cancer Treat Res 2010;153:303–319.
66. Quayle FJ, Benveniste R, DeBenedetti MK, et al. Hereditary medullary thyroid carcinoma in patients greater than 50 years old. Surgery 2004;136:1116–1121.
67. Lips CJ, Landsvater RM, Hoppener JW, et al. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 1994;331:828–835.
68. Niccoli-Sire P, Murat A, Baudin E, et al. Early or prophylactic thyroidectomy in MEN 2/FMTC gene carriers: results in 71 thyroidectomized patients. The French Calcitonin Tumours Study Group (GETC). Eur J Endocrinol 1999;141:468–474.
69. Rodriguez GJ, Balsalobre MD, Pomares F, et al. Prophylactic thyroidectomy in MEN 2A syndrome: experience in a single center. J Am Coll Surg 2002;195:159–166.
70. Skinner MA, Moley JA, Dilley WG, et al. Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. N Engl J Med 2005;353:1105–1113.
71. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;86:5658–5671.
72. Elisei R, Romei C, Renzini G, et al. The timing of total thyroidectomy in RET gene mutation carriers could be personalized and safely planned on the basis of serum calcitonin: 18 years experience at one single center. J Clin Endocrinol Metab 2012;97:426–435.
73. Waguespack SG, Rich TA, Perrier ND, et al. Management of medullary thyroid carcinoma and MEN2 syndromes in childhood. Nat Rev Endocrinol 2011;7:596–607.
74. Moley JF. Medullary thyroid carcinoma: management of lymph node metastases. J Natl Compr Canc Netw 2010;8:549–556.
75. Machens A, Dralle H. Biomarker-based risk stratification for previously untreated medullary thyroid cancer. J Clin Endocrinol Metab 2010;95:2655–2663.
76. Solorzano CC, Evans DB. Same-day ultrasound guidance in reoperations for locally recurrent papillary thyroid cancer. Surgery 2007;142:973–975.
77. Patel SG, Ahnen DJ. Familial colon cancer syndromes: an update of a rapidly evolving field. Curr Gastroenterol Rep 2012;14:428–438.
78. Aretz S, Uhlhaas S, Goergens H, et al. MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype. Int J Cancer 2006;119:807–814.
79. Russell AM, Zhang J, Luz J, et al. Prevalence of MYH germline mutations in Swiss APC mutation-negative polyposis patients. Int J Cancer 2006;118:1937–1940.
80. Jasperson KW. Genetic testing by cancer site: colon (polyposis syndromes). Cancer J 2012;18:328–333.
81. Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 2005;352:1851–1860.
82. Lynch HT, Lynch PM, Lanspa SJ, et al. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet 2009;76:1–18.
83. Vasen HF, Blanco I, Aktan-Collan K, et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut 2013;62:812–823.
84. Niessen RC, Hofstra RM, Westers H, et al. Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes Chromosomes Cancer 2009;48:737–744.
85. Kuiper RP, Vissers LE, Venkatachalam R, et al. Recurrence and variability of germline EPCAM deletions in Lynch syndrome. Hum Mutat 2011;32:407–414.
86. Rumilla K, Schowalter KV, Lindor NM, et al. Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated Lynch syndrome cases. J Mol Diagn 2011;13:93–99.
87. Jasperson KW, Tuohy TM, Neklason DW, et al. Hereditary and familial colon cancer. Gastroenterology 2010;138:2044–2058.
88. Steinhagen E, Markowitz AJ, Guillem JG. How to manage a patient with multiple adenomatous polyps. Surg Oncol Clin N Am 2010;19:711–723.
89. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening. http://www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf. Accessed February 19, 2014.
90. Vasen HF, Moslein G, Alonso A, et al. Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut 2008;57:704–713.
91. Church J. Familial adenomatous polyposis. Surg Oncol Clin N Am 2009;18:585–598.
92. Nieuwenhuis MH, Bulow S, Bjork J, et al. Genotype predicting phenotype in familial adenomatous polyposis: a practical application to the choice of surgery. Dis Colon Rectum 2009;52:1259–1263.
93. Sinha A, Tekkis PP, Rashid S, et al. Risk factors for secondary proctectomy in patients with familial adenomatous polyposis. Br J Surg 2010;97:1710–1715.
94. Koskenvuo L, Renkonen-Sinisalo L, Jarvinen HJ, et al. Risk of cancer and secondary proctectomy after colectomy and ileorectal anastomosis in familial adenomatous polyposis. Int J Colorectal Dis 2014;29:225–230.
95. Remzi FH, Church JM, Bast J, et al. Mucosectomy vs. stapled ileal pouch-anal anastomosis in patients with familial adenomatous polyposis: functional outcome and neoplasia control. Dis Colon Rectum 2001;44:1590–1596.
96. Friederich P, de Jong AE, Mathus-Vliegen LM, et al. Risk of developing adenomas and carcinomas in the ileal pouch in patients with familial adenomatous polyposis. Clin Gastroenterol Hepatol 2008;6:1237–1242.
97. Aziz O, Athanasiou T, Fazio VW, et al. Meta-analysis of observational studies of ileorectal versus ileal pouch-anal anastomosis for familial adenomatous polyposis. Br J Surg 2006;93:407–417.
98. Fazio VW, Kiran RP, Remzi FH, et al. Ileal pouch anal anastomosis: analysis of outcome and quality of life in 3707 patients. Ann Surg 2013;257:679–685.
99. Rajaratnam SG, Eglinton TW, Hider P, et al. Impact of ileal pouch-anal anastomosis on female fertility: meta-analysis and systematic review. Int J Colorectal Dis 2011;26:1365–1374.
100. Bartels SA, D’Hoore A, Cuesta MA, et al. Significantly increased pregnancy rates after laparoscopic restorative proctocolectomy: a cross-sectional study. Ann Surg 2012;256:1045–1048.
101. Beyer-Berjot L, Maggiori L, Birnbaum D, et al. A total laparoscopic approach reduces the infertility rate after ileal pouch-anal anastomosis: a 2-center study. Ann Surg 2013;258:275–282.
102. Steinhagen E, Guillem JG, Chang G, et al. The prevalence of thyroid cancer and benign thyroid disease in patients with familial adenomatous polyposis may be higher than previously recognized. Clin Colorectal Cancer 2012;11:304–308.
103. Steinhagen E, Hui VW, Levy RA, et al. Results of a prospective thyroid ultrasound screening program in adenomatous polyposis patients. Am J Surg [ePub ahead of print].
104. Jarrar AM, Milas M, Mitchell J, et al. Screening for thyroid cancer in patients with familial adenomatous polyposis. Ann Surg 2011;253:515–521.
105. Giardiello FM, Burt RW, Jarvinen H, et al. Familial adenomatous polyposis. In: Bosman FT, Carneiro F, Hruban RH, et al, eds. Classification of Tumours of the Digestive System. Lyon: IARC Press; 2010:147–151.
106. Nieuwenhuis MH, Lefevre JH, Bulow S, et al. Family history, surgery, and APC mutation are risk factors for desmoid tumors in familial adenomatous polyposis: an international cohort study. Dis Colon Rectum 2011;54:1229–1234.
107. Quintini C, Ward G, Shatnawei A, et al. Mortality of intra-abdominal desmoid tumors in patients with familial adenomatous polyposis: a single center review of 154 patients. Ann Surg 2012;255:511–516.
108. Sinha A, Gibbons DC, Phillips RK, et al. Surgical prophylaxis in familial adenomatous polyposis: do pre-existing desmoids outside the abdominal cavity matter? Fam Cancer 2010;9:407–411.
109. Schiessling S, Kihm M, Ganschow P, et al. Desmoid tumour biology in patients with familial adenomatous polyposis coli. Br J Surg 2013;100:694–703.
110. von Roon AC, Tekkis PP, Lovegrove RE, et al. Comparison of outcomes of ileal pouch-anal anastomosis for familial adenomatous polyposis with and without previous ileorectal anastomosis. Br J Surg 2008;95:494–498.
111. Nieuwenhuis MH, Vogt S, Jones N, et al. Evidence for accelerated colorectal adenoma—carcinoma progression in MUTYH-associated polyposis? Gut 2012;61:734–738.
112. Palomaki GE, McClain MR, Melillo S, et al. EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med 2009;11:42–65.
113. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004;96:261–268.
114. Vasen HF, Watson P, Mecklin JP, et al. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999;116:1453–1456.
115. Barnetson RA, Tenesa A, Farrington SM, et al. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med 2006;354:2751–2763.
116. Lee-Kong SA, Markowitz AJ, Glogowski E, et al. Prospective immunohistochemical analysis of primary colorectal cancers for loss of mismatch repair protein expression. Clin Colorectal Cancer 2010;9:255–259.
117. Steinhagen E, Shia J, Markowitz AJ, et al. Systematic immunohistochemistry screening for Lynch syndrome in early age-of-onset colorectal cancer patients undergoing surgical resection. J Am Coll Surg 2012;214:61–67.
118. Heald B, Plesec T, Liu X, et al. Implementation of universal microsatellite instability and immunohistochemistry screening for diagnosing lynch syndrome in a large academic medical center. J Clin Oncol 2013;31:1336–1340.
119. Beamer LC, Grant ML, Espenschied CR, et al. Reflex immunohistochemistry and microsatellite instability testing of colorectal tumors for Lynch syndrome among US cancer programs and follow-up of abnormal results. J Clin Oncol 2012;30:1058–1063.
120. Mvundura M, Grosse SD, Hampel H, et al. The cost-effectiveness of genetic testing strategies for Lynch syndrome among newly diagnosed patients with colorectal cancer. Genet Med 2010;12:93–104.
121. Chen S, Wang W, Lee S, et al. Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA 2006;296:1479–1487.
122. Kastrinos F, Steyerberg EW, Mercado R, et al. The PREMM(1,2,6) model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history. Gastroenterology 2011;140:73–81.
123. Green RC, Parfrey PS, Woods MO, et al. Prediction of Lynch syndrome in consecutive patients with colorectal cancer. J Natl Cancer Inst 2009;101:331–340.
124. Khan O, Blanco A, Conrad P, et al. Performance of Lynch syndrome predictive models in a multi-center US referral population. Am J Gastroenterol 2011;106:1822–1827, quiz 1828.
125. Tresallet C, Brouquet A, Julie C, et al. Evaluation of predictive models in daily practice for the identification of patients with Lynch syndrome. Int J Cancer 2012;130:1367–1377.
126. Kalady MF, McGannon E, Vogel JD, et al. Risk of colorectal adenoma and carcinoma after colectomy for colorectal cancer in patients meeting Amsterdam criteria. Ann Surg 2010;252:507–511, discussion 511–513.
127. Parry S, Win AK, Parry B, et al. Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: the advantage of more extensive colon surgery. Gut 2011;60:950–957.
128. Kalady MF, Lipman J, McGannon E, et al. Risk of colonic neoplasia after proctectomy for rectal cancer in hereditary nonpolyposis colorectal cancer. Ann Surg 2012;255:1121–1125.
129. Cirillo L, Urso ED, Parrinello G, et al. High risk of rectal cancer and of metachronous colorectal cancer in probands of families fulfilling the Amsterdam criteria. Ann Surg 2013;257:900–904.
130. Stupart DA, Goldberg PA, Baigrie RJ, et al. Surgery for colonic cancer in HNPCC: total vs segmental colectomy. Colorectal Dis 2011;13:1395–1399.
131. Maeda T, Cannom RR, Beart RW Jr, et al. Decision model of segmental compared with total abdominal colectomy for colon cancer in hereditary nonpolyposis colorectal cancer. J Clin Oncol 2010;28:1175–1180.
132. Guillem JG, Glogowski E, Moore HG, et al. Single-amplicon MSH2 A636P mutation testing in Ashkenazi Jewish patients with colorectal cancer: role in presurgical management. Ann Surg 2007;245:560–565.
133. Barrow P, Khan M, Lalloo F, et al. Systematic review of the impact of registration and screening on colorectal cancer incidence and mortality in familial adenomatous polyposis and Lynch syndrome. Br J Surg 2013;100:1719–1731.
134. Vasen HF, Abdirahman M, Brohet R, et al. One to 2-year surveillance intervals reduce risk of colorectal cancer in families with Lynch syndrome. Gastroenterology 2010;138:2300–2306.
135. Stuckless S, Green JS, Morgenstern M, et al. Impact of colonoscopic screening in male and female Lynch syndrome carriers with an MSH2 mutation. Clin Genet 2012;82:439–445.
136. Engel C, Rahner N, Schulmann K, et al. Efficacy of annual colonoscopic surveillance in individuals with hereditary nonpolyposis colorectal cancer. Clin Gastroenterol Hepatol 2010;8:174–182.
137. Syngal S, Weeks JC, Schrag D, et al. Benefits of colonoscopic surveillance and prophylactic colectomy in patients with hereditary nonpolyposis colorectal cancer mutations. Ann Intern Med 1998;129:787–796.
138. Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer. Dis Colon Rectum 2014;57(8):1025–1048.